3: Innate & Adaptive Immune System Activation

innate immune system first line of defense

physical barriers: epithelial layers of skin, mucosal/glandular tissues

chemical barriers: soluble substances that have antimicrobial activity or alter pH

2nd line of defense innate immune system

cellular response by tissue-resident immune cells (macrophages, dendritic cells, NK) → induce inflammation & activate adaptive immune cells

list 3 inflammatory responses

phagocytosis

production of molecules w/ antimicrobial activity

recruit fluid & cells to site of infection

how do inflammatory responses benefit the cell

eliminate pathogens/dead cells

promote healing

activate adaptive immunity

does innate or adaptive immunity have a faster response time?

innate

does innate or adaptive immunity have memory response?

adaptive; innate has very small response

how is cellular innate immunity activated?

PRRs on/inside tissue-resident cells bind to PAMPs

are PRRs membrane-bound or intracellular? what types of calls are they expressed on?

both

expressed on myeloid cells, lymphocytes

significance of PRRs on lymphocytes

increase their signaling & cytokine production; don’t activate them

why are PRRs expressed on non-immune cells?

cells need to be able to secrete cytokines & alert immune system

significance of toll-like receptors

one of the most important PRRs found on sentinel immune cells

bind pathogen onto LRRs (leucine-rich repeats) and result in cell activation

describe the process of phagocytosis

1. Phagocyte PRR recognizes PAMP on microbe

2. Phagocyte membrane’s actin filaments rearrange & extend to engulf microbes into phagosomes

3. Phagosomes merge with intracellular lysosomes → activate hydrolytic enzymes which degrade microbes

how do neutrophils induce inflammation and kill pathogens?

1. granules with antimicrobial/cytolytic proteins

2. ROS/RNS (from respiratory burst) that fuse w/ phagosomes

respiratory burst

neutrophils use O2 in environment to produce chemicals (ROS/RNS) to kill pathogens

how is phagocytosis triggered?

opsonization (opsonin receptors)

PRR/PAMP or DAMP interaction

opsonization

phagocyte recognition of proteins on microbial surfaces that enhance phagocytosis

opsonin receptors

bind to microbes and make them appealing to phagocytic cell

(ex: antibodies)

process of inflammation

1. bacteria enters tissue

2. PRRs of tissue-resident macrophages interact w/ bacterial PAMPs → induce secretion of pro-inflammatory chemokines by regular & immune cells

3. neutrophils & phagocytes follow chemokine gradient and induce inflammation

4. vasodilation, extravasation: allow fluid & rolling neutrophils (ROS/NOS) to attack pathogen

3 main APCs

b-cells

dendritic cells

macrophages

how do dendrites (innate immunity) activate adaptive immunity?

1. Sentinels in epithelium

2. Dendritic PRRs bind to PAMPs → upregulate MHC and costimulatory peptides (CD8086)

3. Present self-peptides on MHC-I; exogenous microbes on MHC-II

4. Travel through lymphatics to lymphoid tissue to present antigens to lymphocytes

what is the complement system?

set of 50 serum proteins floating in blood that eliminate pathogens or dying cells and form immune complexes (need to be activated first)

connects innate & adaptive immune system

immune complexes

formed by the complement system

antibodies that aggregate on cell surface → allow easy recognition for macrophages to clear them via phagocytosis

describe complement cascade

1. initiators bind to cell

2. complement molecules cleaved & activated

3. induce: opsonins, anaphylatoxins, membrane attack complex, complement receptors on immune cells

anaphylatoxins

produced via complement molecules, induce systemwide inflammation

membrane attack complex

produced via complement molecules

embed into pathogen membrane, poke holes for fluid entry

complement receptors

on immune cells, bind opsonins that are bound to pathogens & induce phagocytosis

what do all complement molecule activation pathways lead to?

termination: inflammation, opsonization, lysis

complement classical pathway

antibody binds to pathogen, complement molecules bind to antibodies

complement lectin pathway

MBL binds to carbohydrates on bacterial cells, induces complement

complement alternative pathway

spontaneously activated upon infection

how do pAPCs activate T-cells?

1. PRRs bind to antibodies/complement

2. phagocytosis induced, pathogen degraded (lysosomal-mediated mechanism)

3. presents antigenic peptides on MHC (surveillance mechanism to activate T-cells)

MHC locus

region of DNA that expresses MHC-I/II

what is MHC called in humans

HLA (human leukocyte antigen) complex

why does HLA make transplantation so complicated?

HLA is diverse among population b/c it’s a haplotype

MHC-I

glycoproteins expressed on almost all cells

presents endogenous peptides to CD8 T cells

MHC-II

glycoproteins expressed on APCs (macrophages, DCs, B cells)

present exogenous peptides to CD4 T cells

MHC spend most time presenting what?

self-peptides (to indicate cell is healthy)

self-peptide + MHC-I

healthy cell

foreign peptide + MHC-I

cell is infected

engage TC cell

foreign peptide + MHC-II

body is infected

engage TH cells

central tolerance

self peptide in MHC-I/II + developing T cell

testing T-cell for auto-reactivity

occurs in primary lymphoid organs

(if T cell reacts, dies by apoptosis)

peripheral tolerance

displaying self peptide in MHC-I/II to maintain tolerance to self-proteins

occurs in secondary lymphoid organs

(if lymphocyte reacts, dies by apoptosis)

MHC-I presentation pathway (endogenous pathway)

1. virus gets into cell genome & expresses its proteins

2. proteins degraded by proteasome and put into ER w/ MHC-I

3. proteins expressed in MHC-I

4. MHC-I shuttle through golgi complex to surface

MHC-II presentation pathway (exogenous pathway)

1. external materials enter cell via endocytosis/vesicles

2. lysosomal degradation in vesicle

3. vesicle merges w/ another vesicle containing MHC-II and goes to cell surface

describe autocrine mechanism T-cells use for clonal expansion

after activation, T cell produces its own IL-2 & IL-2 receptor → induces proliferation

Three (two)-signal hypothesis

1. TCR signaling (foreign peptide in MHC-II interacts w/ TCR)

2. Costimulatory interaction (CD80/86 on APC binds to CD28 on T-cell; CD80/86 unregulated by PAMP/PRR interaction)

3. Cytokines enhance proliferation and survival (IL-2)

What results from TCR activation?

downstream signaling that activates:
NF-KB
NFAT
AP1

results in: cell survival, proliferation, cell differentiation, effector function

T-cell anergy

T-cell non-responsiveness due to no costimulatory signal

if occurs too much → T-cell exhaustion (won’t respond to any further antigen)

What happens when T cell receives signal 1 and 2?

produces cytokines that enhance proliferation

What do coinhibitory receptors do? Why is it important?

Inhibit costimulation and T-cell activation

Important for maintaining peripheral tolerance & reducing inflammation

(also blocked during cancer treatment)

How does CD28 enhance TCR-enduced proliferation?

increases IL-2 growth factor

Ligands for CD28

CD80 (B7-1)

CD86 (B7-2)

Why are mature DCs the best activators of naive T cells?

They always have some level of CD80/86

How does CTLA-4 work

post-activation, gets up-regulated

binds to CD80/86 w/ higher affinity than CD28, cell no longer gets signal 2 → T-cell anergy

How does Ipilimumab work?

Major cancer therapy

Designed against CTLA-4 and prevents it from binding to CD28, allows T-cell to be active for longer

What is PD-1 (programmed cell death-1)? What does it bind to and what does it result in?

Coinhibitory receptor on B and T cells

binds PD-L1

results in inhibition of T-cell activation

what do interactions between PD-1 and PD-L1 regulate?

differentiation of TREGs (enhances/regulates immune suppressive function)

CTLA-4 and PD-1 binding lead to what?

T-cell anergy/exhaustion

T cell signal 3

T-cell activation shaped by cytokines produced by APCs and T cells

enhances proliferation and survival

Involves polarizing cytokines (determine what type of effector cells T cells become)

what cytokine induces optimal T-cell proliferation? What is its production increased by?

IL-2

TCR and costimulatory signals increase its production

Polarizing cytokines

part of T-cell signal 3

determine what type of effector cells the naive T-cells become

APCs

phagocytic: dendritic cell, macrophage

nonphagocytic: B lymphocytes

How do T-cells obtain rapid proliferation

signals 1 and 2 up regulate:

1. IL-2

2. a-chain of IL2R (most important chain of IL2R)

CD8 cytotoxic T cells

circulate to sites of infection and kill infected cells

CD4 helper T cells

secrete cytokines to regulate activity of other cell types (B cells, macrophages, T cells)

TREG polarizing cytokines and effector function

polarizing cytokines: IL-2, TGF-B

effector function: suppress immune response

TH17 polarizing cytokines and effector function

polarizing cytokines: IL-6, IL-23, TGF-B

effector function: activate neutrophils to combat extracellular pathogens (induce pro-inflammatory state)

TH2 polarizing cytokine and effector function

polarizing cytokines: IL-4

effector function: combats extracellular pathogens (class switch on B cells to IgE)

TH1 polarizing cytokines and effector function

polarizing cytokines: IL-12, IFN-gamma

effector function: respond to intracellular pathogens, activate macrophages

2 major responses from CD4 helper T-cells & define them

T1 response (cell-mediated): intracellular virus binds to intracellular PRR, produces IL-12 → triple-signal causes TH1 cell production → IFN

T2 response (extracellular): extracellular parasite binds to surface PRR, prodouces IL-14 → triple-signal causes TH2 cell production → IL-4/5/13

TH17

Promotes activation of neutrophils to combat extracellular bacteria and fungi

TH2

Promotes activation of B cells to fight extracellular pathogens

TH1

Promotes activation to fight intracellular bacteria and viruses

When do antigen-specific memory T cells remain?

after contraction phase

PAMPs (pathogen-associated molecular patterns)

recurrent molecular patterns of pathogen molecules

DAMPs (damage-associated molecular patterns)

antigens associated with dead or dying cells